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WO2014100080A1 - Combination - Google Patents

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Publication number
WO2014100080A1
WO2014100080A1 PCT/US2013/075937 US2013075937W WO2014100080A1 WO 2014100080 A1 WO2014100080 A1 WO 2014100080A1 US 2013075937 W US2013075937 W US 2013075937W WO 2014100080 A1 WO2014100080 A1 WO 2014100080A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
administered
combination
suitably
days
Prior art date
Application number
PCT/US2013/075937
Other languages
French (fr)
Inventor
Ari M. Melnick
Caretha L. CREASY
Michael T. MCCABE
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Priority to EP13864107.1A priority Critical patent/EP2934531A4/en
Priority to US14/653,404 priority patent/US20150313906A1/en
Publication of WO2014100080A1 publication Critical patent/WO2014100080A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a method of treating cancer and pre-cancerous syndromes in a mammal and to combinations useful in such treatment.
  • the method relates to novel combinations comprising:
  • Bcl-2 inhibitor is selected from:
  • Epigenetic modifications play an important role in the regulation of many cellular processes including cell proliferation, differentiation, and cell survival.
  • Global epigenetic modifications are common in cancer, and include global changes in DNA and/or histone methylation, dysregulation of non-coding RNAs and nucleosome remodeling leading to aberrant activation or inactivation of oncogenes, tumor suppressors and signaling pathways.
  • these epigenetic changes can be reversed through selective inhibition of the enzymes involved.
  • Several methylases involved in histone or DNA methylation are known to be dysregulated in cancer. Thus, selective inhibitors of particular methylases will be useful in the treatment of proliferative diseases such as cancer.
  • EZH2 (enhancer of zeste homolog 2; human EZH2 gene: Cardoso, C, et al; European J of Human Genetics, Vol. 8, No. 3 Pages 174-180, 2000) is the catalytic subunit of the Polycomb Repressor Complex 2 (PRC2) which functions to silence target genes by tri-methylating lysine 27 of histone H3 (H3K27me3).
  • Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.
  • Histones are involved with the structure of the nucleosomes, a 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
  • Increased EZH2 expression has been observed in numerous solid tumors including those of the prostate, breast, skin, bladder, liver, pancreas, head and neck and correlates with cancer aggressiveness, metastasis and poor outcome (Varambally et al., 2002; Kleer et al., 2003; Breuer et al., 2004; Bachmann et al., 2005; Weikert et al., 2005; Sudo et al., 2005; Bachmann et al., 2006).
  • Bcl-2 is the prominent member of a family of proteins that are responsible for dysregulation of apoptosis and prevention of death in cancer cells [Reed J., J Clin Oncoh 999; 17: 2941-2953; and Gross A, Mc Donnell JM, Korsmeyer SJ, Genes
  • Antiapoptotic bcl-2 family members including bcl-xL, and proapoptotic proteins, such as BAD and BAX, interplay with each other to control the pathways leading to the release of cytochrome c from the mitochondrial membrane, the activation of caspase cascade and, finally, to the execution of apoptosis [Reed J., J Clin Oncoh 999; 17: 2941-2953; and Gross A, Mc Donnell JM, Korsmeyer SJ, Genes
  • Bcl-2 overexpression and/or activation and/or translocations have also been correlated with resistance to chemotherapy, to radiotherapy and to development of hormone-resistant tumours, particularly in lymphomas [Jansen B, Schlagbauer-Wadl H, Brown BD et al. Nature Med1998; 4: 232-234; Gieave M, Tolcher A, Miyake H et al. Clin Cancer Res1999; 5: 2891-2898 and Miyake H, Tolcher A, Gieave M. J Nail Cancer Inst2000; 92: 34-41].
  • Bcl-2 overexpression results in the up- regulation of VEGF expression with increased neoangiogenesis in human cancer xenografts [Biroccio A, Candiloro A, Housinglese M et al. FASEB J2000; 14: 852-680].
  • Bcl-2 may be a relevant target for cancer therapy. It would be useful to provide a novel therapy which provides more effective and/or enhanced treatment of an individual suffering the effects of cancer and pre-cancerous syndromes.
  • the current invention concerns the combination of a specified EZH2 inhibitor and a Bcl-2 inhibitor for the treatment of cancer and pre-cancerous syndromes.
  • One embodiment of this invention provides a combination comprising an EZH2 inhibiting compound selected from:
  • narmaceutically acceptable salt thereof narmaceutically acceptable salt thereof; and a Bcl-2 inhibitor, suitably selected from:
  • Figure - 1 depicts the dose reduction index (DRI) based on an analysis of cell viability in a panel of diffuse large B-cell lymphoma (DLBCL) cells exposed to increasing concentrations of Compound B followed by ABT737 or obatoclax.
  • DRBCL diffuse large B-cell lymphoma
  • the present invention relates to combinations that exhibit antiproliferative activity.
  • the method relates to methods of treating cancer and pre-cancerous syndromes by the co-administration of an EZH2 inhibiting compound selected from:
  • Compound A which compound is represented by Structure I:
  • Compound B 1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1 -piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof, (collectively, hereinafter "Compound B”), which compound is represented by Structure II:
  • Compound C N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H- pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof, (collectively, hereinafter "Compound C”), which compound is represented by Structure III:
  • Bcl-2 inhibitor suitably selected from:
  • Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US201 1/035336, having an International filing date of May 5, 201 1 , International Publication Number W01 1/140324 and an
  • Compound A is the compound of Example 270.
  • Compound A can be prepared as described in International Application No.
  • Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US201 1/035340, having an International filing date of May 5, 201 1 , International Publication Number W01 1/140325 and an International Publication date of November 10, 201 1 , the entire disclosure of which is hereby incorporated by reference, Compound B is the compound of Example 126. Compound B can be prepared as described in International Application No.
  • Compound C is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US2012/033648, having an International filing date of April 13, 2012, International Publication Number WO12/142504 and an International Publication date of October 18, 2012, the entire disclosure of which is hereby incorporated by reference, Compound C is the compound of Example 44.
  • Compound C can be prepared as described in International Application No.
  • Bcl-2 inhibitors described below are known, known to inhibit Bcl-2, and are made by known methods:
  • the administration of a therapeutically effective amount of the combinations of the invention are advantageous over the individual component compounds in that the combinations will provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds.
  • the compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or
  • the compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • the solvent used is water.
  • contemplated herein is a method of treating cancer using a combination of the invention where the EZH2 and BCL2 compounds of the invention are administered as pro-drugs.
  • Pharmaceutically acceptable pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
  • day refers to a time within one calendar day which begins at midnight and ends at the following midnight.
  • treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy is also contemplated thereby.
  • prevention is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • “combination” and derivatives thereof, as used herein is meant either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of an EZH2 compound and a BCL2 compound of the invention.
  • the compounds are administered in a close time proximity to each other.
  • both compounds are administered intravenously (IV).
  • one compound is administered orally and the other is administered by IV.
  • both compounds are administered orally.
  • the combination kit as used herein is meant the pharmaceutical composition or compositions that are used to administer an EZH2 compound and a BCL2 compound, according to the invention.
  • the combination kit can contain an EZH2 compound and a BCL2 compound of the invention, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain an EZH2 compound and a BCL2 compound of the invention, in separate pharmaceutical compositions.
  • the combination kit can comprise an EZH2 compound and a BCL2 compound of the invention, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • a combination kit comprising the components: an EZH2 compound of the invention, in association with a pharmaceutically acceptable carrier; and
  • a BCL2 compound of the invention in association with a pharmaceutically acceptable carrier.
  • the combination kit comprises: a first container comprising an EZH2 compound of the invention, in association with a pharmaceutically acceptable carrier; and
  • a second container comprising a BCL2 compound of the invention, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • the "combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
  • loading dose as used herein will be understood to mean a single dose or short duration regimen of an EZH2 compound and a BCL2 compound of the invention having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug.
  • a short duration regimen for use herein will be from: 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 3 days; suitably for three days; suitably for two days; suitably for one day.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug.
  • the "loading dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day).
  • the "loading dose” will be administered once a day.
  • the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times;
  • the loading dose will be administered for from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
  • maintenance dose as used herein will be understood to mean a dose that is serially administered (for example, at least twice), and which is intended to either slowly raise blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level.
  • the maintenance dose is generally administered once per day and the daily dose of the maintenance dose is lower than the total daily dose of the loading dose.
  • the combinations of this invention are administered within a "specified period”.
  • the specified period can include simultaneous administration.
  • the specified period refers to timing of the administration of an EZH2 compound and a BCL2 compound of the invention during a single day.
  • the specified period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.
  • the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suit
  • the compounds when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
  • duration of time and derivatives thereof, as used herein is meant that both compounds of the invention are administered within a “specified period” for an indicated number of consecutive days, optionally followed by a number of consecutive days where only one of the component compounds is administered.
  • both compounds will be administered within a specified period for at least 1 day - in this case, the duration of time will be at least 1 day; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably,
  • both compounds are administered within a specified period for over 30 days, the treatment is considered chronic treatment and will continue until an altering event, such as a reassessment in cancer status or a change in the condition of the patient, warrants a modification to the protocol.
  • both compounds will be administered within a specified period for at least 1 day, followed by the administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment,
  • both compounds will be administered within a specified period for from 1 to 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 3 to 7 consecutive days.
  • both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 1 to 4 consecutive days.
  • both compounds will be administered within a specified period for 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for 2 consecutive days.
  • both compounds will be administered within a specified period for 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 3 to 7 consecutive days.
  • both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period an EZH2 compound of the invention will be administered alone.
  • both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period an EZH2 compound of the invention will be administered alone.
  • both compounds will be administered within a specified period for at least 1 day, followed by the administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment,
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 6 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days - in
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days
  • the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days
  • the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days
  • the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days
  • the duration of time will be at least 37 consecutive days.
  • both compounds will be administered within a specified period for from 1 to 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 3 to 7 consecutive days.
  • both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 1 to 4 consecutive days.
  • both compounds will be administered within a specified period for 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for 2 consecutive days.
  • both compounds will be administered within a specified period for 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 3 to 7 consecutive days.
  • both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period a BCL2 compound of the invention will be administered alone.
  • both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period a BCL2 compound of the invention will be administered alone.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 3 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 3 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 1 day during a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 1 day during a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 5 days over a 14 day period, and during the other days of the 14 day period the EZH2 compound will be administered alone.
  • this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
  • an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 5 days over a 14 day period, and during the other days of the 14 day period the BCL2 compound will be administered alone.
  • this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
  • the compounds are not administered during a "specified period", they are administered sequentially.
  • sequential administration and derivates thereof, as used herein is meant that one of an EZH2 compound and a BCL2 compound of the invention is administered for one or more consecutive days and the other of an EZH2 compound and a BCL2 compound of the invention is subsequently administered for one or more consecutive days.
  • a drug holiday utilized between the sequential administration of one of an EZH2 compound and a BCL2 compound of the invention and the other of an EZH2 compound and a BCL2 compound of the invention.
  • a drug holiday is a period of days after the sequential administration of one of an EZH2 compound and a BCL2 compound of the invention and before the administration of the other of an EZH2 compound and a BCL2 compound of the invention where neither compound is administered.
  • a “drug holiday” is suitably a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
  • one of an EZH2 compound and a BCL2 compound of the invention is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 30 consecutive days.
  • one of an EZH2 compound and a BCL2 compound of the invention is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 21 consecutive days.
  • one of an EZH2 compound and a BCL2 compound of the invention is
  • an EZH2 compound and a BCL2 compound of the invention is administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 14 consecutive days.
  • one of an EZH2 compound and a BCL2 compound of the invention is administered for from 2 to 7 consecutive days, followed by a drug holiday of from 2 to 10 days, followed by
  • a BCL2 compound will be administered first in the sequence, followed by an optional drug holiday, followed by administration of an EZH2 compound.
  • a BCL2 compound is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of an EZH2 compound for from 1 to 21 consecutive days.
  • a BCL2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of an EZH2 compound for from 3 to 21 consecutive days.
  • a BCL2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of an EZH2 compound for from 3 to 21 consecutive days.
  • Compound B is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A for 14 consecutive days.
  • a BCL2 compound is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of an EZH2 compound A for 14 consecutive days.
  • a BCL2 compound is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of an EZH2 compound for 7 consecutive days.
  • a BCL2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of an EZH2 compound A for 7 consecutive days.
  • a BCL2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of an EZH2 compound for 3 consecutive days.
  • a BCL2 compound is administered for from 1 to 14 consecutive days, followed by an optional drug holiday, followed by administration of an EZH2 compound from 1 to 3 days a week for one or two weeks.
  • a BCL2 compound is administered for from 1 to 3 days a week for from one to four weeks, followed by an optional drug holiday, followed by administration of an EZH2 compound from 1 to 3 days a week for one or two weeks.
  • an EZH2 compound will be administered first in the sequence, followed by an optional drug holiday, followed by administration of a BCL2 compound.
  • an EZH2 compound is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of a BCL2 compound for from 1 to 21 consecutive days.
  • an EZH2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of a BCL2 compound for from 3 to 21 consecutive days.
  • an EZH2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of a BCL2 compound for from 3 to 21 consecutive days.
  • an EZH2 compound is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of a BCL2 compound for 14 consecutive days.
  • an EZH2 compound is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of a BCL2 compound for 14 consecutive days.
  • an EZH2 compound is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of a BCL2 compound for 7 consecutive days.
  • an EZH2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of a BCL2 compound for 7 consecutive days.
  • an EZH2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of a BCL2 compound for 3 consecutive days.
  • an EZH2 compound is administered for 7 consecutive days, followed by administration of a BCL2 compound for 1 day.
  • an EZH2 compound is administered for 6 consecutive days, followed by administration of a BCL2 compound for 1 day.
  • an EZH2 compound is administered for 1 day, followed by administration of a BCL2 compound for 7 consecutive days.
  • an EZH2 compound is administered for 1 day, followed by administration of a BCL2 compound for 6 consecutive days.
  • an EZH2 compound is administered from 1 to 3 days a week for one or two weeks followed by an optional drug holiday, followed by administration of a BCL2 compound for from 1 to 14 consecutive days.
  • an EZH2 compound is administered for from 1 to 3 days a week for one or two weeks, followed by an optional drug holiday, followed by administration of a BCL2 compound from 1 to 3 days a week for from one to four weeks.
  • a "specified period” administration and a “sequential” administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
  • the EZH2 compound administered as part of the combination according to the present invention will be an IV dose, suitably selected from about 200mg to about 3000mg, suitably formulated with Captisol®, suitably formulated with 10% Captisol®.
  • the selected amount of the EZH2 Compound is administered on different days twice a week, suitably twice a week for one week, suitably twice a week for two weeks, suitably twice a week for three weeks.
  • the administration of the EZH2 Compound will begin as a loading dose.
  • the amount of BCL2 compound administered as part of the combination according to the present invention will be an oral formulation, suitably an IV formulation.
  • the administration of Compound B will begin as a loading dose.
  • all amounts specified for an EZH2 compound and a BCL2 compound of the invention are indicated as the administered amount of free or unsalted compound per dose.
  • the method of the present invention may also be employed with other therapeutic methods of cancer treatment.
  • the combinations of the present invention may be co-administered with at least one other active ingredient known to be useful in the treatment of cancer.
  • the term further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer or precancerous syndromes.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-microtubule agents such as
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anticancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5p,20-epoxy-1 ,2 ⁇ ,4,7 ⁇ , 10 ⁇ , 13a-hexa-hydroxytax-1 1 -en-9-one 4, 10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 1 1 :273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin.
  • Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-ferf-butyl ester, 13-ester with 5p-20-epoxy-1 ,2a,4,7p,10p,13a-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine vincaleukoblastine, 22-oxo-, sulfate
  • ONCOVIN® an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R * ,R * )-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed
  • DTIC-Dome® Commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12
  • naphthacenedione hydrochloride is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.
  • Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • Doxorubicin (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]- 8-glycoloyl, 7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside]
  • VePESID® an injectable solution or capsules
  • VP-16 an injectable solution or capsules
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
  • Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4- (1 H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-1-p-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-1 ,7-dihydro-6H-purine-6-thione
  • TABLOID® Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of
  • choriocarcinoma meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression leucopenia
  • thrombocytopenia, and anemia are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin described below.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
  • Topotecan HCI (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • the dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
  • camptothecin derivative of Formula A including the racemic mixture (R,S) form as well as the R and S enantiomers:
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and
  • prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors
  • progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma
  • estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy
  • anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective
  • GnRH gonadotropin-releasing hormone
  • LH leutinizing hormone
  • FSH follicle stimulating hormone
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
  • protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain.
  • Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • IGFI insulin growth
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69.
  • a VEGFR inhibitor suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochlor
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt.
  • This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001.
  • Pazopanib is implicated in the treatment of cancer and ocular
  • the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases.
  • Non-receptor tyrosine kinases for use in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such nonreceptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases akt kinase family members
  • PDK1 and TGF beta receptor kinases IkB kinase family
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000),
  • the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor.
  • a MEK inhibitor for example, N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo- phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1- yl]phenyl ⁇ acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No.
  • N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl ⁇ acetamide can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
  • the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor.
  • a B-Raf inhibitor e.g., /V- ⁇ 3-[5-(2-Amino-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference.
  • N- ⁇ (1 S)-2-amino-1 -[(3,4- difluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxamide or a pharmaceutically acceptable salt thereof which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference.
  • N- ⁇ (1 S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl ⁇ - 5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2-furancarboxamide is the compound of example 224 and can be prepared as described in International Application No.
  • the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor.
  • an Akt inhibitor / ⁇ /- ⁇ (1 S)-2-amino-1-[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference.
  • ⁇ /- ⁇ (1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl ⁇ -5- chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt.
  • the salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.
  • Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541 -1545.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Ras Oncogene Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
  • Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
  • Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
  • non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alpha v beta 3
  • endostatin and angiostatin non-RTK
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I).
  • immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to
  • Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle.
  • a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • CDKs cyclin dependent kinases
  • examples of cyclin dependent kinases including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • p21 WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin- dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)).
  • HDAC Histone deacetylase
  • Vorinostat including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).
  • Vorinostat has the following chemical structure and name:
  • Romidepsin has the following chemical structure and name:
  • Panobinostat including pharmaceutically acceptable salts thereof.
  • Panobinostat has the following chemical structure and name:
  • Valproic acid has the following chemical structure and name:
  • Mocetinostat has the following chemical structure and name:
  • HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-21 16, particularly the compounds of table 3 therein as indicated below.
  • proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein.
  • proteasome inhibitors are marketed or are being studied in the treatment of cancer. Suitable proteasome inhibitors for use in combination herein include: 1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-1 1.
  • Bortezomib has the followin chemical structure and name:
  • Disulfiram including pharmaceutically acceptable salts thereof.
  • Disulfiram has the following chemical structure and name:
  • Epigallocatechin gallate has the following chemical structure and name:
  • Salinosporamide A including pharmaceutically acceptable salts thereof.
  • Salinosporamide A has the following chemical structure and name:
  • Carfilzomib including pharmaceutically acceptable salts thereof. Kuhn et al, Blood, 2007, 1 10:3281-3290.
  • Carfilzomib has the following chemical structure and name:
  • Hsp70s and Hsp90s are families of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include:
  • 17-AAG(Geldanamycin) has the following chemical structure and name:
  • Radicicol has the following chemical structure and name:
  • Inhibitors of cancer metabolism Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg Effect.
  • TCA tricarboxylic acid
  • Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell.
  • the enzyme has been shown to be upregulated in many tumor types.
  • the alteration of glucose metabolism described in the Warburg effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.
  • FAS fatty acid synthase
  • Inhibitors of cancer metabolism including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention.
  • the cancer treatment method of the claimed invention includes the co-administration a combination of the current invention and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents,
  • topoisomerase II inhibitors antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • the invention further provides pharmaceutical compositions, which include an EZH2 compound and/or a BCL2 compound of the invention, and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing an EZH2 compound and/or a BCL2 compound of the invention with one or more pharmaceutically acceptable carriers. As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • An EZH2 compound and a BCL2 compound of the invention may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the
  • each of the agents administered may be administered by the same or different routes and that the EZH2 compound and BCL2 compound may be compounded together in a pharmaceutical composition/formulation.
  • the EZH2 compound and BCL2 compound of the invention are administered in separate pharmaceutical compositions.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier may include a prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, suitably, may be from about 25 mg to about 1 g per dosage unit.
  • the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • therapeutically effective amounts of the combinations of the invention are administered to a human.
  • the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: lymphoma, follicular lymphomas, leukemia, brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease,
  • Lhermitte-Duclos disease breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: lymphoma, follicular lymphomas, leukemia, brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease,
  • Lhermitte-Duclos disease breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from lymphoma, follicular lymphomas, leukemia, ovarian, breast, pancreatic and prostate.
  • the present invention relates to a method for treating or lessening the severity of lymphoma, follicular lymphomas and leukemia.
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • MGUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • This invention provides a combination comprising an EZH2 inhibitor selected from:
  • Bcl-2 inhibitor is selected from:
  • compositions comprising the same, a combination kit comprising the same, the use of such
  • the combinations of the present invention are tested for efficacy, advantageous and synergistic properties according to known procedures.
  • the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to the following combination cell proliferation assays.
  • Cells are plated in 384- well plates at 500 cells/well in culture media appropriate for each cell type, supplemented with 10% FBS and 1 % penicillin/streptomycin, and incubated overnight at 37°C, 5% C0 2 .
  • Cells are treated in a grid manner with dilution of Compound A (20 dilutions, including no compound, of 2-fold dilutions starting from 1 -20 mM depending of compound) from left to right on 384-well plate; and also treated with Compound B (20 dilutions, including no compound, of 2-fold dilutions starting from 1 -20 mM depending of compound) from top to bottom on 384-well plate; and incubated as above for a further 72 hours. In some instances compounds are added in a staggered manner and incubation time can be extended up to 7 days. Cell growth is measured using CellTiter-Glo® reagent according to the manufacturer's protocol and signals are read on a PerkinElmer EnVisionTM reader set for luminescence mode with a 0.5-second read. Data are analyzed as described below.
  • the cellular response is determined for each compound and/or compound combination using a 4- or 6-parameter curve fit of cell viability against concentration using the I DBS XLfit plug-in for Microsoft Excel software and determining the concentration required for 50% inhibition of cell growth (glC 50 ). Background correction is made by subtraction of values from wells containing no cells.
  • CI Combination Index
  • EHSA Excess Over Highest Single Agent
  • EOBIiss Excess Over Bliss
  • DLBCL cell lines (WSU-DLCL2, SU-DHL-6, SU-DHL-4, Pfeiffer, OCI-LY-7, OCI-LY-1 and Farage) were exposed to 5 concentrations of Compound B for 6 days followed by 5 concentrations of ABT-737 (Selleck) or Obatoclax (Selleck) for an additional 48 h and analyzed for cell viability using a fluorometric resazurin reduction method (CellTiter-Blue, Promega) and trypan blue automatic method (TC10, BioRad).
  • a fluorometric resazurin reduction method CellTiter-Blue, Promega
  • trypan blue automatic method TC10, BioRad
  • Fluorescence (Ex560nm / Em590nm) was determined with the Synergy4 microplate reader (BioTek). The number of viable cells was calculated by using the linear least-squares regression of the standard curve. The fluorescence was determined for three replicates per treatment condition and normalized to their respective controls. To quantify the effect of the sensitization, the dose reduction index (DRI) at GI90 was calculated using CompuSyn software.
  • DRI dose reduction index
  • An oral dosage form for administering a combination of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table III, below.
  • sucrose, microcrystalline cellulose and the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • An IV form for administering a component of the present invention is produced by stirring 1 .5% by weight of Obatoclax in 10% by volume in water.
  • An IV form for administering a component of the present invention is produced by stirring 1 .5% by weight of A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl- 1-[(1 S)-1 -methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide
  • DLBCL cell lines (KARP-422, SU-DHL-6, Pfeiffer, WSU-DLCL2, and Farage) were pre-treated with 1 ⁇ , 500 nM, 250 nM, 100 nM, 50 nM, or 25 nM of Compound A or vehicle alone (DMSO) for 72 hours, at which time the cells were plated into a 384-well plate at a predetermined optimal seeding density. The following day, cells were treated with the same concentration of Compound A used in the pre-treatment, and a 20-point two-fold dilution series of ABT-263, ABT-737 or 0.15% DMSO. Concentrations tested for ABT-263 and ABT-737 ranged from 36.7 mM to 70 pM.
  • CTG CellTiter-Glo
  • chemiluminescent signal was detected with a TECAN Safire2 microplate reader.
  • CTG estimates cell number through detection of cellular ATP levels.
  • an untreated plate of cells was harvested at the time of compound addition (T 0 ) to quantify the starting number of cells.
  • CTG values were expressed as a percent of the T 0 value and plotted against compound concentration. Data were fit with a four-parameter equation to generate a concentration response curve and the
  • DLBCL cell lines were pretreated with Compound A for 3 days followed by a 6 day co-treatment with a BCL-2 inhibitor (ABT-737 and ABT-263) and Compound A. Concentrations of Compound A were chosen for each cell line that would not have effects on cell proliferation (McCabe et al., Nature 2012, 492:108-1 12). The results are described in Table VII below and summarized as follows:

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Abstract

The present invention relates to a method of treating cancer and pre-cancerous syndromes in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering: (i) an EZH2 inhibitor selected from: N-[4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1 S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide, or a pharmaceutically acceptable salt thereof; 1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H-pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof; and (ii) a Bcl-2 inhibitor, to a human in need thereof.

Description

COMBINATION
FIELD OF THE INVENTION
The present invention relates to a method of treating cancer and pre-cancerous syndromes in a mammal and to combinations useful in such treatment. In particular, the method relates to novel combinations comprising:
(i) an EZH2 inhibitor selected from:
A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1 S)-1 - methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide, or a
pharmaceutically acceptable salt thereof;
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1 -piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; and
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H- pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof; and
Bcl-2 inhibitor. Suitably the Bcl-2 inhibitor is selected from
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, and methods of using such combinations in the treatment of cancer and pre-cancerous syndromes. BACKGROUND OF THE INVENTION
Epigenetic modifications play an important role in the regulation of many cellular processes including cell proliferation, differentiation, and cell survival. Global epigenetic modifications are common in cancer, and include global changes in DNA and/or histone methylation, dysregulation of non-coding RNAs and nucleosome remodeling leading to aberrant activation or inactivation of oncogenes, tumor suppressors and signaling pathways. However, unlike genetic mutations which arise in cancer, these epigenetic changes can be reversed through selective inhibition of the enzymes involved. Several methylases involved in histone or DNA methylation are known to be dysregulated in cancer. Thus, selective inhibitors of particular methylases will be useful in the treatment of proliferative diseases such as cancer.
EZH2 (enhancer of zeste homolog 2; human EZH2 gene: Cardoso, C, et al; European J of Human Genetics, Vol. 8, No. 3 Pages 174-180, 2000) is the catalytic subunit of the Polycomb Repressor Complex 2 (PRC2) which functions to silence target genes by tri-methylating lysine 27 of histone H3 (H3K27me3). Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.
Featuring a main globular domain and a long N-terminal tail, Histones are involved with the structure of the nucleosomes, a 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
Increased EZH2 expression has been observed in numerous solid tumors including those of the prostate, breast, skin, bladder, liver, pancreas, head and neck and correlates with cancer aggressiveness, metastasis and poor outcome (Varambally et al., 2002; Kleer et al., 2003; Breuer et al., 2004; Bachmann et al., 2005; Weikert et al., 2005; Sudo et al., 2005; Bachmann et al., 2006). For instance, there is a greater risk of recurrence after prostatectomy in tumors expressing high levels of EZH2, increased metastasis, shorter disease-free survival and increased death in breast cancer patients with high EZH2 levels (Varambally et al., 2002; Kleer et al., 2003). More recently, inactivating mutations in UTX (ubiquitously transcribed tetratricopeptixe repeats X), a H3K27 demethylase which functions in opposition to EZH2, have been identified in multiple solid and hematological tumor types (including renal, glioblastoma, esophageal, breast, colon, non-small cell lung, small cell lung, bladder, multiple myeloma, and chronic myeloid leukemia tumors), and low UTX levels correlate with poor survival in breast cancer suggesting that loss of UTX function leads to increased H3K27me3 and repression of target genes (Wang et al., 2010). Together, these data suggest that increased H3K27me3 levels contribute to cancer aggressiveness in many tumor types and that inhibition of EZH2 activity may provide therapeutic benefit.
Numerous studies have reported that direct knockdown of EZH2 via siRNA or shRNA or indirect loss of EZH2 via treatment with the SAH hydrolase inhibitor 3- deazaneplanocin A (DZNep) decreases cancer cell line proliferation and invasion in vitro and tumor growth in vivo (Gonzalez et al., 2008, GBM 2009). While the precise mechanism by which aberrant EZH2 activity leads to cancer progression is not known, many EZH2 target genes are tumor suppressors suggesting that loss of tumor suppressor function is a key mechanism. In addition, EZH2 overexpression in immortalized or primary epithelial cells promotes anchorage independent growth and invasion and requires EZH2 catalytic activity.(Kleer et al., 2003; Cao et al., 2008).
Inhibition of EZH2 activity has been associated with decreasing cellular proliferation and invasion.
Bcl-2 is the prominent member of a family of proteins that are responsible for dysregulation of apoptosis and prevention of death in cancer cells [Reed J., J Clin Oncoh 999; 17: 2941-2953; and Gross A, Mc Donnell JM, Korsmeyer SJ, Genes
Dev1999; 13: 1899-191 1 ]. Antiapoptotic bcl-2 family members, including bcl-xL, and proapoptotic proteins, such as BAD and BAX, interplay with each other to control the pathways leading to the release of cytochrome c from the mitochondrial membrane, the activation of caspase cascade and, finally, to the execution of apoptosis [Reed J., J Clin Oncoh 999; 17: 2941-2953; and Gross A, Mc Donnell JM, Korsmeyer SJ, Genes
Dev1999; 13: 1899-191 1 ]. Bcl-2 overexpression and/or activation and/or translocations have also been correlated with resistance to chemotherapy, to radiotherapy and to development of hormone-resistant tumours, particularly in lymphomas [Jansen B, Schlagbauer-Wadl H, Brown BD et al. Nature Med1998; 4: 232-234; Gieave M, Tolcher A, Miyake H et al. Clin Cancer Res1999; 5: 2891-2898 and Miyake H, Tolcher A, Gieave M. J Nail Cancer Inst2000; 92: 34-41].
Moreover, it has been suggested that Bcl-2 overexpression results in the up- regulation of VEGF expression with increased neoangiogenesis in human cancer xenografts [Biroccio A, Candiloro A, Mottolese M et al. FASEB J2000; 14: 852-680].
Evidance suggest that Bcl-2 may be a relevant target for cancer therapy. It would be useful to provide a novel therapy which provides more effective and/or enhanced treatment of an individual suffering the effects of cancer and pre-cancerous syndromes. The current invention concerns the combination of a specified EZH2 inhibitor and a Bcl-2 inhibitor for the treatment of cancer and pre-cancerous syndromes.
SUMMARY OF THE INVENTION
One embodiment of this invention provides a combination comprising an EZH2 inhibiting compound selected from:
(i) a compound of Structure (I):
Figure imgf000006_0001
pharmaceutically acceptable salt thereof; compound of Structure (II):
Figure imgf000006_0002
(II)
narmaceutically acceptable salt thereof; or (iii) a compound of Structure
Figure imgf000007_0001
(III)
narmaceutically acceptable salt thereof; and a Bcl-2 inhibitor, suitably selected from:
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof.
One embodiment of this invention provides a method of treating cancer and precancerous syndromes in a human in need thereof which comprises the in vivo
administration of a therapeutically effective amount of a combination of A/-[4,6-dimethyl-2 oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 S)-1-methylpropyl]-6-[6-(1-piperazinyl)- 3- pyridinyl]-1 /-/-indole-4-carboxamide, or a pharmaceutically acceptable salt thereof, and a Bcl-2 inhibitor, to such human.
One embodiment of this invention provides a method of treating cancer and precancerous syndromes in a human in need thereof which comprises the in vivo
administration of a therapeutically effective amount of a combination of 1-(1-methylethyl)- A/-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2-(4-methyl-1-piperazinyl)-
4- pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof, and a Bcl-2 inhibitor, to such human, wherein the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
One embodiment of this invention provides a method of treating cancer and precancerous syndromes in a human in need thereof which comprises the in vivo
administration of a therapeutically effective amount of a combination of N-((4,6-dimethyl- 2-OXO-1 , 2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2/-/-pyran-4-yl)amino)-4-mehtyl- 4'-(morpholinomethyl)-[1 ,1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a Bcl-2 inhibitor, to such human, wherein the compounds of the combination are administered sequentially.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure - 1 Figure 1 depicts the dose reduction index (DRI) based on an analysis of cell viability in a panel of diffuse large B-cell lymphoma (DLBCL) cells exposed to increasing concentrations of Compound B followed by ABT737 or obatoclax.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to combinations that exhibit antiproliferative activity. Suitably, the method relates to methods of treating cancer and pre-cancerous syndromes by the co-administration of an EZH2 inhibiting compound selected from:
A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1 S)-1 - methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide, or a
pharmaceutically acceptable salt thereof, (collectively, hereinafter "Compound A"), which compound is represented by Structure I:
Figure imgf000009_0001
(I);
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1 -piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof, (collectively, hereinafter "Compound B"), which compound is represented by Structure II:
Figure imgf000009_0002
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H- pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof, (collectively, hereinafter "Compound C"), which compound is represented by Structure III:
Figure imgf000010_0001
(in);
and a Bcl-2 inhibitor, suitably selected from:
Figure imgf000010_0002
or a pharmaceutically acceptable salt thereof.
Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US201 1/035336, having an International filing date of May 5, 201 1 , International Publication Number W01 1/140324 and an
International Publication date of November 10, 201 1 , the entire disclosure of which is hereby incorporated by reference, Compound A is the compound of Example 270. Compound A can be prepared as described in International Application No.
PCT/US201 1/035336.
Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US201 1/035340, having an International filing date of May 5, 201 1 , International Publication Number W01 1/140325 and an International Publication date of November 10, 201 1 , the entire disclosure of which is hereby incorporated by reference, Compound B is the compound of Example 126. Compound B can be prepared as described in International Application No.
PCT/US201 1/035340.
Compound C is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of EZH2 activity, particularly in treatment of cancer, in International Application No. PCT/US2012/033648, having an International filing date of April 13, 2012, International Publication Number WO12/142504 and an International Publication date of October 18, 2012, the entire disclosure of which is hereby incorporated by reference, Compound C is the compound of Example 44.
Compound C can be prepared as described in International Application No.
PCT/US2012/033648.
The Bcl-2 inhibitors described below are known, known to inhibit Bcl-2, and are made by known methods:
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof.
The administration of a therapeutically effective amount of the combinations of the invention are advantageous over the individual component compounds in that the combinations will provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds.
The compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or
enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of EZH2 and BCL2 compounds of the invention.
The compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Suitably the solvent used is a pharmaceutically acceptable solvent. Suitably the solvent used is water.
The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.
Also, contemplated herein is a method of treating cancer using a combination of the invention where the EZH2 and BCL2 compounds of the invention are administered as pro-drugs. Pharmaceutically acceptable pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
When referring to a dosing protocol, the term "day", "per day" and the like, refer to a time within one calendar day which begins at midnight and ends at the following midnight.
By the term "treating" and derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy is also contemplated thereby. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. By the term "combination" and derivatives thereof, as used herein is meant either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of an EZH2 compound and a BCL2 compound of the invention. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered intravenously (IV). Suitably, one compound is administered orally and the other is administered by IV. Suitably, both compounds are administered orally.
By the term "combination kit" as used herein is meant the pharmaceutical composition or compositions that are used to administer an EZH2 compound and a BCL2 compound, according to the invention. When both compounds are administered simultaneously, the combination kit can contain an EZH2 compound and a BCL2 compound of the invention, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain an EZH2 compound and a BCL2 compound of the invention, in separate pharmaceutical compositions. The combination kit can comprise an EZH2 compound and a BCL2 compound of the invention, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
In one aspect there is provided a combination kit comprising the components: an EZH2 compound of the invention, in association with a pharmaceutically acceptable carrier; and
a BCL2 compound of the invention, in association with a pharmaceutically acceptable carrier.
In one embodiment of the invention the combination kit comprises the following components:
an EZH2 compound of the invention, in association with a pharmaceutically acceptable carrier; and
a BCL2 compound of the invention, in association with a pharmaceutically acceptable carrier,
wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
In one embodiment the combination kit comprises: a first container comprising an EZH2 compound of the invention, in association with a pharmaceutically acceptable carrier; and
a second container comprising a BCL2 compound of the invention, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
The "combination kit" can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
Unless otherwise defined, in all dosing protocols described herein, the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
The term "loading dose" as used herein will be understood to mean a single dose or short duration regimen of an EZH2 compound and a BCL2 compound of the invention having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug. Suitably, a short duration regimen for use herein will be from: 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 3 days; suitably for three days; suitably for two days; suitably for one day. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug. The "loading dose" can be administered once per day, or more than once per day (e.g., up to 4 times per day). Suitably the "loading dose" will be administered once a day. Suitably, the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times;
suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times. Suitably, the loading dose will be administered for from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
The term "maintenance dose" as used herein will be understood to mean a dose that is serially administered (for example, at least twice), and which is intended to either slowly raise blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level. The maintenance dose is generally administered once per day and the daily dose of the maintenance dose is lower than the total daily dose of the loading dose.
Suitably the combinations of this invention are administered within a "specified period".
By the term "specified period" and derivatives thereof, as used herein is meant the interval of time between the administration of one of an EZH2 compound and a BCL2 compound of the invention, and the other of an EZH2 compound and a BCL2 compound of the invention. Unless otherwise defined, the specified period can include simultaneous administration. When both compounds of the invention are administered once a day the specified period refers to timing of the administration of an EZH2 compound and a BCL2 compound of the invention during a single day. When one or both compounds of the invention are administered more than once a day, the specified period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.
Suitably, if the compounds are administered within a "specified period" and not administered simultaneously, they are both administered within about 24 hours of each other - in this case, the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will both be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will both be administered within about 4 hours of each other - in this case, the specified period will be about 4 hours; suitably they will both be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suitably they will both be administered within about 1 hour of each other - in this case, the specified period will be about 1 hour. As used herein, the administration of an EZH2 compound and a BCL2 compound of the invention in less than about 45 minutes apart is considered simultaneous administration.
Suitably, when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
By the term "duration of time" and derivatives thereof, as used herein is meant that both compounds of the invention are administered within a "specified period" for an indicated number of consecutive days, optionally followed by a number of consecutive days where only one of the component compounds is administered.
Regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day - in this case, the duration of time will be at least 1 day; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days. When, during the course of treatment, both compounds are administered within a specified period for over 30 days, the treatment is considered chronic treatment and will continue until an altering event, such as a reassessment in cancer status or a change in the condition of the patient, warrants a modification to the protocol.
Further regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by the administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 5 days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 6 days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of an EZH2 compound of the invention alone for at least 7 days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 6 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 6 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of an EZH2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 37 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 1 to 4 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 5 consecutive days, followed by administration of an EZH2 compound of the invention alone for 2 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 consecutive days, followed by administration of an EZH2 compound of the invention alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period an EZH2 compound of the invention will be administered alone. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period an EZH2 compound of the invention will be administered alone.
Further regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by the administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 5 days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 6 days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of a BCL2 compound of the invention alone for at least 7 days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 6 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 5 consecutive days
- in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 6 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 3 consecutive days
- in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days
- in this case, the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days
- in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 3 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 4 consecutive days
- in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 5 consecutive days - in this case, the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 2 consecutive days
- in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days - in this case, the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of a BCL2 compound of the invention alone for at least 7 consecutive days
- in this case, the duration of time will be at least 37 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 1 to 4 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 5 consecutive days, followed by administration of a BCL2 compound of the invention alone for 2 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 consecutive days, followed by administration of a BCL2 compound of the invention alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period a BCL2 compound of the invention will be administered alone. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period a BCL2 compound of the invention will be administered alone.
Further regarding "specified period" administration:
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous
administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous
administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 3 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration. Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 3 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 1 day during a 7 day period, and during the other days of the 7 day period the EZH2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for 1 day during a 7 day period, and during the other days of the 7 day period the BCL2 compound will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 5 days over a 14 day period, and during the other days of the 14 day period the EZH2 compound will be administered alone. Suitably, this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
Suitably, during the course of treatment, an EZH2 compound and a BCL2 compound of the invention will be administered within a specified period for from 1 to 5 days over a 14 day period, and during the other days of the 14 day period the BCL2 compound will be administered alone. Suitably, this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration. Suitably, if the compounds are not administered during a "specified period", they are administered sequentially. By the term "sequential administration", and derivates thereof, as used herein is meant that one of an EZH2 compound and a BCL2 compound of the invention is administered for one or more consecutive days and the other of an EZH2 compound and a BCL2 compound of the invention is subsequently administered for one or more consecutive days. Also, contemplated herein is a drug holiday utilized between the sequential administration of one of an EZH2 compound and a BCL2 compound of the invention and the other of an EZH2 compound and a BCL2 compound of the invention. As used herein, when referring to sequential administration, a drug holiday is a period of days after the sequential administration of one of an EZH2 compound and a BCL2 compound of the invention and before the administration of the other of an EZH2 compound and a BCL2 compound of the invention where neither compound is administered.
As used herein, a "drug holiday" is suitably a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
Regarding sequential administration:
Suitably, one of an EZH2 compound and a BCL2 compound of the invention is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 30 consecutive days. Suitably, one of an EZH2 compound and a BCL2 compound of the invention is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 21 consecutive days. Suitably, one of an EZH2 compound and a BCL2 compound of the invention is
administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 1 to 14 consecutive days. Suitably, one of an EZH2 compound and a BCL2 compound of the invention is administered for from 2 to 7 consecutive days, followed by a drug holiday of from 2 to 10 days, followed by
administration of the other of an EZH2 compound and a BCL2 compound of the invention for from 2 to 7 consecutive days.
Suitably, a BCL2 compound will be administered first in the sequence, followed by an optional drug holiday, followed by administration of an EZH2 compound. Suitably, a BCL2 compound is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of an EZH2 compound for from 1 to 21 consecutive days. Suitably, a BCL2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of an EZH2 compound for from 3 to 21 consecutive days. Suitably, a BCL2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of an EZH2 compound for from 3 to 21 consecutive days. Suitably, Compound B is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A for 14 consecutive days. Suitably, a BCL2 compound is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of an EZH2 compound A for 14 consecutive days. Suitably, a BCL2 compound is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of an EZH2 compound for 7 consecutive days. Suitably, a BCL2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of an EZH2 compound A for 7 consecutive days. Suitably, a BCL2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of an EZH2 compound for 3 consecutive days. Suitably, a BCL2 compound is administered for from 1 to 14 consecutive days, followed by an optional drug holiday, followed by administration of an EZH2 compound from 1 to 3 days a week for one or two weeks. Suitably, a BCL2 compound is administered for from 1 to 3 days a week for from one to four weeks, followed by an optional drug holiday, followed by administration of an EZH2 compound from 1 to 3 days a week for one or two weeks.
Suitably, an EZH2 compound will be administered first in the sequence, followed by an optional drug holiday, followed by administration of a BCL2 compound. Suitably, an EZH2 compound is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of a BCL2 compound for from 1 to 21 consecutive days. Suitably, an EZH2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of a BCL2 compound for from 3 to 21 consecutive days. Suitably, an EZH2 compound is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of a BCL2 compound for from 3 to 21 consecutive days. Suitably, an EZH2 compound is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of a BCL2 compound for 14 consecutive days. Suitably, an EZH2 compound is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of a BCL2 compound for 14 consecutive days. Suitably, an EZH2 compound is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of a BCL2 compound for 7 consecutive days.
Suitably, an EZH2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of a BCL2 compound for 7 consecutive days. Suitably, an EZH2 compound is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of a BCL2 compound for 3 consecutive days. Suitably, an EZH2 compound is administered for 7 consecutive days, followed by administration of a BCL2 compound for 1 day. Suitably, an EZH2 compound is administered for 6 consecutive days, followed by administration of a BCL2 compound for 1 day. Suitably, an EZH2 compound is administered for 1 day, followed by administration of a BCL2 compound for 7 consecutive days. Suitably, an EZH2 compound is administered for 1 day, followed by administration of a BCL2 compound for 6 consecutive days. Suitably, an EZH2 compound is administered from 1 to 3 days a week for one or two weeks followed by an optional drug holiday, followed by administration of a BCL2 compound for from 1 to 14 consecutive days. Suitably, an EZH2 compound is administered for from 1 to 3 days a week for one or two weeks, followed by an optional drug holiday, followed by administration of a BCL2 compound from 1 to 3 days a week for from one to four weeks.
It is understood that a "specified period" administration and a "sequential" administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
Suitably, the EZH2 compound administered as part of the combination according to the present invention will be an IV dose, suitably selected from about 200mg to about 3000mg, suitably formulated with Captisol®, suitably formulated with 10% Captisol®.
Suitably, the selected amount of the EZH2 Compound is administered on different days twice a week, suitably twice a week for one week, suitably twice a week for two weeks, suitably twice a week for three weeks. Suitably, the administration of the EZH2 Compound will begin as a loading dose.
Suitably, the amount of BCL2 compound administered as part of the combination according to the present invention will be an oral formulation, suitably an IV formulation. Suitably, the administration of Compound B will begin as a loading dose. As used herein, all amounts specified for an EZH2 compound and a BCL2 compound of the invention are indicated as the administered amount of free or unsalted compound per dose.
The method of the present invention may also be employed with other therapeutic methods of cancer treatment.
The combinations of the present invention may be co-administered with at least one other active ingredient known to be useful in the treatment of cancer.
By co-administration with other anti-neoplastic agents is meant either
simultaneous administration or any manner of separate sequential administration of a combination of the invention, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer or precancerous syndromes, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer or precancerous syndromes. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.
Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented combinations are chemotherapeutic agents.
Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
Diterpenoids, which are derived from natural sources, are phase specific anticancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 5p,20-epoxy-1 ,2α,4,7β, 10β, 13a-hexa-hydroxytax-1 1 -en-9-one 4, 10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325.
1971 ), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561 -1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435- 10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 1 1 :273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin.
Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide,. 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-ferf-butyl ester, 13-ester with 5p-20-epoxy-1 ,2a,4,7p,10p,13a-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
Carboplatin, platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed
myelosuppression is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-1 -triazeno)-imidazole-4-carboxamide, is
commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12
naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]- 8-glycoloyl, 7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-1-p-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.
Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of
choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia,
thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-20-camptothecin described below.
Irinotecan HCI, (4S)-4,1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)
carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
Also of interest, is the camptothecin derivative of Formula A following, including the racemic mixture (R,S) form as well as the R and S enantiomers:
Figure imgf000038_0001
known by the chemical name "7-(4-methylpiperazino-methylene)-10, 1 1-ethylenedioxy-
20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10, 1 1 - ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)-
10, 1 1 -ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos.
6,063,923; 5,342,947; 5,559,235; 5,491 ,237 and pending U.S. patent Application No.
08/977,217 filed November 24, 1997.
Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and
prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.
Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain.
Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth.
Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London. Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.
Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001.
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient®.
Pazopanib is implicated in the treatment of cancer and ocular
diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in
combination with pazopanib.
Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such nonreceptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
Immunology. 15: 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32. Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000),
Biochemical Pharmacology, 60. 1 101-1 107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391 ; Pearce, L.R et al. Nature Reviews Molecular Cell Biology (2010) 1 1 , 9-22. and Martinez-lacaci, L, et al, Int. J. Cancer (2000), 88(1 ), 44-52.
Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo- phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1- yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No. PCT/JP2005/01 1082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121 142 and an International Publication date of December 22, 2005, the entire disclosure of which is hereby incorporated by reference. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Suitably, /V-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference. /\/-{3-[5-(2-Amino-4- pyrimidinyl)-2-(1 , 1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682. Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1 S)-2-amino-1 -[(3,4- difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2- furancarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}- 5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2-furancarboxamide is the compound of example 224 and can be prepared as described in International Application No.
PCT/US2008/053269.
Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, /\/-{(1 S)-2-amino-1-[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5- chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is the compound of example 96 and can be prepared as described in International Application No.
PCT/US2008/053269. Suitably, Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5- chloro-4-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.
Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541 -1545.
Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to
chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21 WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin- dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)).
Compounds that are known to induce expression of p21WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon et al., Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors are implicated in the transcriptional activation of p21WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (Jan 2002)), and are suitable cell cycle signaling inhibitors for use in combination herein. Examples of such HDAC inhibitors include:
1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).
Vorinostat has the following chemical structure and name:
Figure imgf000045_0001
/V-hydroxy-A/'-phenyl-octanediamide
2. Romidepsin, including pharmaceutically acceptable salts thereof.
Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.
Romidepsin, has the following chemical structure and name:
Figure imgf000045_0002
(1 S,4S,7Z, 10S, 16E.21 R)-7-ethylidene-4,21 -di(propan-2-yl)-2-oxa-12, 13-dithia- 5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9, 19,22-pentone
3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4): 315-322 (2007).
Panobinostat, has the following chemical structure and name:
Figure imgf000045_0003
(2£)-/V-hydroxy-3-[4-({[2-(2-methyl-1 H-indol-3- yl)ethyl]amino}methyl)phenyl]acrylamide 4. Valproic acid, including pharmaceutically acceptable salts thereof.
Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001 ).
Valproic acid, has the following chemical structure and name:
Figure imgf000046_0001
2-propylpentanoic acid
5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 21 1 -221 (2009).
Mocetinostat, has the following chemical structure and name:
Figure imgf000046_0002
A/-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide
Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-21 16, particularly the compounds of table 3 therein as indicated below.
Figure imgf000047_0001
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Several proteasome inhibitors are marketed or are being studied in the treatment of cancer. Suitable proteasome inhibitors for use in combination herein include: 1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-1 1.
Bortezomib has the followin chemical structure and name:
Figure imgf000048_0001
[(1 R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2- ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid.
2. Disulfiram, including pharmaceutically acceptable salts thereof.
Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.
Disulfiram has the following chemical structure and name:
Figure imgf000048_0002
", 1 "'-[disulfanediylbis(carbonothioylnitrilo)]tetraethane.
3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74.
Epigallocatechin gallate has the following chemical structure and name:
Figure imgf000048_0003
[(2/?,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate.
4. Salinosporamide A, including pharmaceutically acceptable salts thereof.
Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7. Salinosporamide A has the following chemical structure and name:
Figure imgf000049_0001
(4R,5S)-4-(2-chloroethyl)-1-((1 S)-cyclohex-2-enyl(hydroxy)methyl) -5-methyl-6-oxa-2- azabicyclo3.2.0heptane-3,7-dione.
5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn et al, Blood, 2007, 1 10:3281-3290.
Carfilzomib has the following chemical structure and name:
Figure imgf000049_0002
(S)-4-methyl-N-((S)-1-(((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1 -oxopentan-2-yl)amino)-
1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4- phenylbutanamido)pentanamide.
The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins (Hsp90s) are families of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include:
1. 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood. 2003 Sep 1 ;102(5):1824-32.
17-AAG(Geldanamycin) has the following chemical structure and name:
Figure imgf000050_0001
17-(Allylamino)-17-demethoxygeldanamycin.
2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al.,
Mol Cell Endocrinol. 2002, 188,47-54)
Radicicol has the following chemical structure and name:
Figure imgf000050_0002
(1 aR,2Z,4E, 14R, 15aR)-8-chloro-9, 1 1 -dihydroxy-14-methyl-15,15a-dihydro-1 aH- benzo[c]oxireno[2,3-k][1 ]oxacyclotetradecine-6, 12(7H,14H)-dione.
Inhibitors of cancer metabolism - Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg Effect.
Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell. The enzyme has been shown to be upregulated in many tumor types. The alteration of glucose metabolism described in the Warburg effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.
D. A. Tennant et. al., Nature Reviews, 2010, 267. P. Leder, et. al., Cancer Cell, 2006, 9, 425.
High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance.
Alii et al. Oncogene (2005) 24, 39-46. doi:10.1038
Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention.
In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a combination of the current invention and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents,
topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
While it is possible that, for use in therapy, therapeutically effective amounts of the combinations of the present invention may be administered as the raw chemical, it is preferable to present the combinations as a pharmaceutical composition or compositions. Accordingly, the invention further provides pharmaceutical compositions, which include an EZH2 compound and/or a BCL2 compound of the invention, and one or more pharmaceutically acceptable carriers. The combinations of the present invention are as described above. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing an EZH2 compound and/or a BCL2 compound of the invention with one or more pharmaceutically acceptable carriers. As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
An EZH2 compound and a BCL2 compound of the invention may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the
combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the EZH2 compound and BCL2 compound may be compounded together in a pharmaceutical composition/formulation. Suitably, the EZH2 compound and BCL2 compound of the invention are administered in separate pharmaceutical compositions.
The compounds or combinations of the current invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier may include a prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, suitably, may be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
It should be understood that in addition to the ingredients mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
As indicated, therapeutically effective amounts of the combinations of the invention (an EZH2 compound in combination with a BCL2 compound of the invention) are administered to a human. Typically, the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician.
Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: lymphoma, follicular lymphomas, leukemia, brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease,
Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: lymphoma, follicular lymphomas, leukemia, brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease,
Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from lymphoma, follicular lymphomas, leukemia, ovarian, breast, pancreatic and prostate.
Suitably, the present invention relates to a method for treating or lessening the severity of lymphoma, follicular lymphomas and leukemia. Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
This invention provides a combination comprising an EZH2 inhibitor selected from:
A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1 S)-1 - methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide, or a
pharmaceutically acceptable salt thereof;
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1 -piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; and
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H- pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof;
and a Bcl-2 inhibitor, suitably the Bcl-2 inhibitor is selected from:
Figure imgf000054_0001
or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, a combination kit comprising the same, the use of such
combinations in the treatment of cancer and pre-cancerous syndromes, the use of such combinations in the manufacture of a medicament, and the use of such combinations in the manufacture of a medicament to treat cancer and pre-cancerous syndromes.
The combinations of the present invention are tested for efficacy, advantageous and synergistic properties according to known procedures. Suitably, the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to the following combination cell proliferation assays. Cells are plated in 384- well plates at 500 cells/well in culture media appropriate for each cell type, supplemented with 10% FBS and 1 % penicillin/streptomycin, and incubated overnight at 37°C, 5% C02. Cells are treated in a grid manner with dilution of Compound A (20 dilutions, including no compound, of 2-fold dilutions starting from 1 -20 mM depending of compound) from left to right on 384-well plate; and also treated with Compound B (20 dilutions, including no compound, of 2-fold dilutions starting from 1 -20 mM depending of compound) from top to bottom on 384-well plate; and incubated as above for a further 72 hours. In some instances compounds are added in a staggered manner and incubation time can be extended up to 7 days. Cell growth is measured using CellTiter-Glo® reagent according to the manufacturer's protocol and signals are read on a PerkinElmer EnVision™ reader set for luminescence mode with a 0.5-second read. Data are analyzed as described below.
Results are expressed as a percentage of the t=0 value and plotted against compound(s) concentration. The t=0 value is normalized to 100% and represents the number of cells present at the time of compound addition. The cellular response is determined for each compound and/or compound combination using a 4- or 6-parameter curve fit of cell viability against concentration using the I DBS XLfit plug-in for Microsoft Excel software and determining the concentration required for 50% inhibition of cell growth (glC50). Background correction is made by subtraction of values from wells containing no cells. For each drug combination a Combination Index (CI), Excess Over Highest Single Agent (EOHSA) and Excess Over Bliss (EOBIiss) are calculated according to known methods such as described in Chou and Talalay (1984) Advances in Enzyme Regulation, 22, 37 to 55; and Berenbaum, MC (1981 ) Adv. Cancer Research, 35, 269- 335.
The data for Figure I was not obtained according to the above assay. Instead, DLBCL cell lines (WSU-DLCL2, SU-DHL-6, SU-DHL-4, Pfeiffer, OCI-LY-7, OCI-LY-1 and Farage) were exposed to 5 concentrations of Compound B for 6 days followed by 5 concentrations of ABT-737 (Selleck) or Obatoclax (Selleck) for an additional 48 h and analyzed for cell viability using a fluorometric resazurin reduction method (CellTiter-Blue, Promega) and trypan blue automatic method (TC10, BioRad). Fluorescence (Ex560nm / Em590nm) was determined with the Synergy4 microplate reader (BioTek). The number of viable cells was calculated by using the linear least-squares regression of the standard curve. The fluorescence was determined for three replicates per treatment condition and normalized to their respective controls. To quantify the effect of the sensitization, the dose reduction index (DRI) at GI90 was calculated using CompuSyn software. The DRI is a measure of how many fold the dose of each drug in a combination may be reduced at a given effect level compared with the doses of each drug alone and is based on the equation DRI = (Dx)1 / (D)1 , where (Dx)1 represents the dose of drug 1 for a given effect (x) and where (D)1 represents the dose of drug 1 given in combination to reach the same effect (x).
The combinations of the present invention are tested in the above assays to determine advantageous therapeutic utility in treating cancer.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
Experimental Details
Example 1 - Capsule Composition
An oral dosage form for administering a combination of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
Table I
INGREDIENTS AMOUNTS
A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3- 200mg
methyl-1 -[(1 S)-1-methylpropyl]-6-[6-(1 -piperazinyl)-3- pyridinyl]-1 H-indole-4-carboxamide (Compound A)
ABT-737 (BCL2 inhibitor) 50mg
Mannitol 250 mg
Talc 125 mg
Magnesium Stearate 8 mg Example 2 - Capsule Composition
An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
Table II
INGREDIENTS AMOUNTS
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro- 200mg
3-pryidinyl)methyl]-6-[2-(4-methyl-1 -piperazinyl)-4-pyridinyl]- 1 H-indazole-4-carboxamide (Compound B)
Mannitol 150mg
Talc 16mg
Magnesium Stearate 4mg
Example 3 - Capsule Composition
An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table III, below.
Table III
INGREDIENTS AMOUNTS
Gossypol (BCL2 inhibitor) 50mg
Mannitol 150mg
Talc 12mg
Magnesium Stearate 8mg
Example 4 - Tablet Composition
The sucrose, microcrystalline cellulose and the compounds of the invented combination, as shown in Table IV below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet. Table IV
INGREDIENTS AMOUNTS
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5- 200mg
(ethyl(tetahydro-2H-pyran-4-yl)amino)-4-mehtyl-4'- (morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide
(Compound C)
Obatoclax (BCL2 inhibitor) 50mg
Microcrystalline cellulose 300mg
sucrose 10mg
starch 40mg
talc 20mg
stearic acid 5mg
Example 5 - Tablet Composition
The sucrose, microcrystalline cellulose and one of the compounds of the invented combination, as shown in Table V below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
Table V
INGREDIENTS AMOUNTS
/v-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3- 200mg
methyl-1 -[(1 S)-1-methylpropyl]-6-[6-(1 -piperazinyl)-3- pyridinyl]-1 H-indole-4-carboxamide (Compound A)
Microcrystalline cellulose 200mg
sucrose 4mg
starch 2mg
talc 1 mg
stearic acid 0.5mg
Example 6 - Tablet Composition
The sucrose, microcrystalline cellulose and one of the compounds of the invented combination, as shown in Table VI below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
Table VI
INGREDIENTS AMOUNTS
Obatoclax (BCL2 inhibitor) 30mg
Microcrystalline cellulose 300mg sucrose 40mg
starch 20mg
talc 10mg
stearic acid 5mg
Example 7 - Intravenous IV Composition
An IV form for administering a component of the present invention is produced by stirring 1 .5% by weight of Obatoclax in 10% by volume in water.
Example 8 - Intravenous IV Composition
An IV form for administering a component of the present invention is produced by stirring 1 .5% by weight of A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl- 1-[(1 S)-1 -methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide
(Compound A) in 10% by volume Captisol® in water.
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.
Example 9 - Further Synergy Experiments
Method:
DLBCL cell lines (KARP-422, SU-DHL-6, Pfeiffer, WSU-DLCL2, and Farage) were pre-treated with 1 μΜ, 500 nM, 250 nM, 100 nM, 50 nM, or 25 nM of Compound A or vehicle alone (DMSO) for 72 hours, at which time the cells were plated into a 384-well plate at a predetermined optimal seeding density. The following day, cells were treated with the same concentration of Compound A used in the pre-treatment, and a 20-point two-fold dilution series of ABT-263, ABT-737 or 0.15% DMSO. Concentrations tested for ABT-263 and ABT-737 ranged from 36.7 mM to 70 pM. Plates were incubated for 6 days at 37°C in 5% C02. Cells were then lysed with CellTiter-Glo (CTG) (Promega) according to the manufacturer's protocol and chemiluminescent signal was detected with a TECAN Safire2 microplate reader. CTG estimates cell number through detection of cellular ATP levels. In addition, an untreated plate of cells was harvested at the time of compound addition (T0) to quantify the starting number of cells. CTG values were expressed as a percent of the T0 value and plotted against compound concentration. Data were fit with a four-parameter equation to generate a concentration response curve and the
concentration of Compound A required to inhibit 50% of growth (glC50) was determined.
Results:
To investigate whether pre-treatment of DLBCL cell lines with Compound A would sensitize cells to BCL-2 inhibitors, DLBCL cell lines were pretreated with Compound A for 3 days followed by a 6 day co-treatment with a BCL-2 inhibitor (ABT-737 and ABT-263) and Compound A. Concentrations of Compound A were chosen for each cell line that would not have effects on cell proliferation (McCabe et al., Nature 2012, 492:108-1 12). The results are described in Table VII below and summarized as follows:
• In Farage, a DLBCL line harboring WT EZH2, a 43 and 19 -fold shift in glC50 potency with 1 μΜ pretreatment with Compound A for 72 hours was observed with ABT-263 and ABT-737, respectively.
• In KARPAS-422, a DLBCL line harboring a Y641 N mutation in EZH2, a 423 and 304 fold shift in glC50 potency with 500 nM pretreatment with Compound A for 72 hours was observed with ABT-263 and ABT-737, respectively.
• In SU-DHL-6, a DLBCL line harboring a Y641 N mutation in EZH2, a 31 and 12 fold shift in glC50 potency with 250 nM pretreatment with Compound A for 72 hours was observed with the ABT-263 and ABT-737, respectively.
• In Pfeiffer, a DLBCL line harboring A677G mutation in EZH2, a 5 and 7 fold shift in glC50 potency with 50 nM pretreatment with Compound A for 72 hours was observed with the ABT-263 and ABT-737, respectively.
• In WSU-DLCL-2, a DLBCL line harboring a Y641 F mutation in EZH2, no
significant shift in glC50 with 250 nM pretreatment with Compound A for 72 hours was observed with ABT-263 or ABT-737, respectively.
Table VII.
Fold shift in Fold shift in
EZH2
BCL2 Compound y potency
Cell Line mutation giCso potenc
Inhibitor A treatment (nM) over ABT- over ABT- status
263 alone 737 alone
Farage WT ABT-263 455
Farage WT ABT-263 1 μΜ 1 1 43
Farage WT ABT-737 — 4708
Farage WT ABT-737 1 uM 246 19
KARPAS-
Y641 N ABT-263 169
422 KARPAS-
Y641N ABT-263 100 nM 60 2.8 422
KARPAS-
Y641N ABT-263 500 nM 0.4 423 422
KARPAS-
Y641N ABT-737 334
422
KARPAS-
Y641N ABT-737 100 nM 78 4.3 422
KARPAS-
Y641N ABT-737 500 nM 1.1 304 422
SU-DHL-6 Y641N ABT-263 518
SU-DHL-6 Y641N ABT-263 250 nM 17 31
SU-DHL-6 Y641N ABT-737 1334
SU-DHL-6 Y641N ABT-737 250 nM 110 12
Pfeiffer A677G ABT-263 553
Pfeiffer A677G ABT-263 25 nM 142 3.9
Pfeiffer A677G ABT-263 50 nM 112 4.9
Pfeiffer A677G ABT-737 2917
Pfeiffer A677G ABT-737 25 nM 633 4.6
Pfeiffer A677G ABT-737 50 nM 393 7.4
WSU-
Y641F ABT-263 464
DLCL2
WSU-
Y641F ABT-263 250 nM 1153 0.4 DLCL2
WSU-
Y641F ABT-737 1412
DLCL2
WSU-
Y641F ABT-737 250 nM 971 1.5 DLCL2

Claims

We claim:
1. A combination comprising:
(i) an EZH2 inhibitor selected from:
A/-[4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1 S)-1 - methylpropyl]-6-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide, or a
pharmaceutically acceptable salt thereof;
1-(1-methylethyl)-/V-[(6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pryidinyl)methyl]-6-[2- (4-methyl-1 -piperazinyl)-4-pyridinyl]-1 H-indazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; and
N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetahydro-2H- pyran-4-yl)amino)-4-mehtyl-4'-(morpholinomethyl)-[1 , 1 '-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt thereof; and
(ii) a Bcl-2 inhibitor, suitably selected from:
Figure imgf000062_0001
or a pharmaceutically acceptable salt thereof.
2. A combination according to claim 1 where the EZH2 inhibiting compound is in the form of a pharmaceutically acceptable salt and the BCL2 inhibiting compound in the form of a pharmaceutically acceptable salt.
3. A combination kit comprising a combination according to claim 1 or claim 2 together with a pharmaceutically acceptable carrier or carriers.
4. A combination according to claim 1 or claim 2 or of a combination kit according to claim 3 where the amount of the compound of the EZH2 inhibiting compound is an amount suitable for intravenous administration from 1 to 3 times per week for from 1 to 4 weeks and the BCL2 inhibiting compound is an amount suitable for administration from 1 to 3 times per week for from 1 to 4 weeks.
5. Use of a combination according to claim 1 or claim 2 or of a combination kit according to claim 3 or of a combination or combination kit according to claim 4 in the manufacture of a medicament or medicaments for the treatment of cancer and/or precancerous syndromes in a human.
6. A combination or combination kit as claimed in any one of claims 1 to 4 for use in the treatment of cancer or pre-cancerous syndromes.
7. A combination or combination kit according to claim 7 wherein an amount of EZH2 inhibiting compound, is suitable for administration once per day, and the amount of BCL2 inhibiting compound, is suitable for administration once per day.
8. A combination or combination kit according to claim 7 wherein the EZH2 inhibiting compound and the BCL2 inhibiting compound, are administered within 12 hours of each other for from 1 to 3 days during a week and the BCL2 inhibiting compound is administered alone during the other days of the week, optionally followed by one or more cycles of repeat dosing.
9. A combination or combination kit according to claim 4 wherein the EZH2 inhibiting compound and the BCL2 inhibiting compound are administered sequentially.
10. A combination or combination kit according to claim 10 wherein the EZH2 inhibiting compound is administered first for one or two weeks, followed by an optional drug holiday, followed by administration of the BCL2 inhibiting compound.
1 1 . A combination or combination kit according to claim 10 wherein the EZH2 inhibiting compound and the BCL2 inhibiting compound, are administered for at least two cycles.
12. A combination or combination kit according to claim 7 or claim 8 wherein the EZH2 inhibiting compound is first administered in a loading dose for from 1 to 3 days followed by maintenance dose administration of the compound, and/or the BCL2 inhibiting compound is first administered in a loading dose for from 1 to 3 days followed by maintenance dose administration of the compound.
13. A combination or combination kit according to claim 10 wherein the BCL2 inhibiting compound is administered first for from one to four weeks, followed by an optional drug holiday, followed by administration of the EZH2 inhibiting compound.
14. A use according to claim 5, or a combination or combination kit according to any one of claims 4 and 6 to 14, wherein the cancer is selected from lymphoma, follicular lymphomas, leukemia, ovarian, breast, pancreatic, lymphoma, leukemia and prostate.
15. A use according to claim 5, or a combination or combination kit according to any one of claims 4 and 6 to 14, wherein the cancer is selected from lymphoma, follicular lymphomas and leukemia.
16. A use according to claim 5, or a combination or combination kit according to any one of claims 4 and 6 to 14, wherein the cancer is diffuse large B-cell lymphoma.
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